Real-world experience with ruxolitinib in myelofibrosis

Ruxolitinib is a Janus kinase (JAK) 1 and JAK 2 inhibitor approved for primary and secondary intermediate-/high-risk myelofibrosis (MF). The approval in 2011 was based on the results of the phase III trials COMFORT-I (NCT00952289) and COMFORT-II (NCT00934544). A total of 301 patients were treated with ruxolitinib orally, twice a day, with a starting dose depending on their baseline platelet count.¹

Primary results demonstrated that daily treatment with ruxolitinib significantly reduced spleen volume, improved MF-related symptoms and quality of life, and was associated with prolonged overall survival (OS). After a longer follow-up, it was observed that the risk of death was reduced by 30% among patients randomized to ruxolitinib compared with patients in the control arms (median OS, 5.3 vs 3.8 years; HR, 0.7; 95% CI, 0.54–0.91; p = 0.0065). The positive impact on OS was even more evident when censoring patients in the control arm who crossed over to ruxolitinib treatment (median OS, 5.3 vs 2.4 years; HR, 0.53; 95% CI, 0.36–0.78; p = 0.0013).²

At the American Society of Clinical Oncology (ASCO) 2020 Virtual Annual Meeting, several studies were published addressing the use of ruxolitinib in the real world (RW) in patients with primary or secondary MF. This article provides a summary of the key results.^3–5

RW data confirm that ruxolitinib significantly reduces the risk of death in primary MF³

Gustavo Rivero from Baylor College of Medicine, Houston, US, reported the mortality rates of patients with primary MF registered at the Veterans Integrated Service Network. The following data are from cohorts of 244 and 1,005 patients diagnosed before and after ruxolitinib approval, respectively, with intermediate- or high-risk primary MF.

Patient characteristics and main results are summarized in Table 1. This retrospective analysis observed a 47% reduction in risk of death after ruxolitinib was established as a standard of care for these patients (HR, 0.53; p < 0.001). Nevertheless, other patient and treatment factors might have influenced the improvement of OS and need to be further explored.

Table 1. Patient characteristics and mortality rates reported from patients diagnosed with primary MF before and after ruxolitinib approval³

Dose modification and treatment discontinuation are higher during the first 6 months of ruxolitinib in RW clinical practice^4,5

The initial dose of ruxolitinib is prescribed according to baseline platelet counts, i.e., 5, 15, or 20 mg twice daily for 50–100, 100–200, or > 200 × 10⁹/L, respectively. Platelet count is repeated every 2–4 weeks to adjust the dosing until disease stabilization, and it can be further augmented or reduced based on safety and efficacy.¹ Therefore, dose modification is frequent during the first month of treatment, and when not well adjusted, it can lead to treatment discontinuation.

Aaron Gerds, from Cleveland Clinic Taussig Cancer Institute, Cleveland, US, retrospectively analyzed the results of ruxolitinib in 104 patients with primary or secondary MF treated at multiple community oncology clinics.  After a median follow-up of 23.5 months since treatment initiation, they observed that 40.4% of patients needed a dose modification in the first 6 months of therapy. Of those, 76.2% were dose reductions, mainly due to low hemoglobin (8–10 g/dL) or low platelet count (50–75 × 10⁹/L). Patients who did not require a dose adjustment tended to be younger, started at higher initial doses of ruxolitinib, and had fewer treatment discontinuations within the first 6 months of treatment (Table 2).

Overall, in RW practice, 64.4% of patients discontinued ruxolitinib after a median time of 11.0 months, which indicates the need for additional therapies for patients with MF.

Table 2. Differences between patients with or without dose modifications during the first 6 months of treatment with ruxolitinib⁴

JAK inhibition rechallenge is feasible in patients who previously discontinued ruxolitinib⁵

Naveen Pemmaraju, MD Anderson Cancer Center, Houston, US, and colleagues suspected that there were relevant differences between data reported in the COMFORT trials and RW clinical practice. To further describe treatment patterns and clinical outcomes, they retrospectively studied medical patient charts from two patient care data sources: Cardinal Health Oncology Provider Extended Network and HealthCore Integrated Research Environment.

They identified 26 patients with primary or secondary MF who interrupted their treatment with ruxolitinib. Half of the cases discontinued ruxolitinib within the first 3 months of therapy (median treatment duration was 110–123 days). 

Three patients reported ruxolitinib discontinuation due to disease progression/no response/loss of response, while 15 patients interrupted the treatment due to adverse events (nine for thrombocytopenia, six for anemia).⁵

All patients included in this study restarted ruxolitinib therapy at some point. Interestingly, the median retreatment duration was longer than the first time on treatment (median retreatment duration 166–196 days) and MF-related symptoms and spleen size improved in about 40% of patients. The investigators explain the clinical improvements after ruxolitinib retreatment as being due to premature discontinuation of the first exposure, impeding full JAK inhibition and its benefits.⁵

Conclusions

Until recently, ruxolitinib has been the only drug approved for the treatment of patients with primary or secondary MF. Despite being widely used, these studies showed high discontinuation and dose-modification rates within the first 6 months after ruxolitinib treatment initiation, while retreatment may still be possible in some patients. This may indicate a lack of a consensus on optimal administration of ruxolitinib in the real world, which could in part be due to the difficulty to differentiate between ruxolitinib resistance and intolerance. For further details, see also the consensus by the Canadian MPN Group and recommendations based on results of the JAKARTA study.

In 2019, the U.S. Food and Drug Administration (FDA) approved a new agent for the treatment of MF: fedratinib, a JAK2 inhibitor effective in treatment-naïve patients and those who did not benefit from ruxolitinib.⁶ However, management of relevant neurological and gastrointestinal adverse events is still under evaluation, as well as the feasibility and methodology to switch patients from ruxolitinib to fedratinib.